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Wednesday, October 29, 2008

As reported last week, Merck Serono, ZymoGenetics’ partner on the autoimmune disease candidate, is discontinuing development in lupus nephritis due to an increased risk of infection.

ZymoGenetics had hoped an accelerated filing for atacicept could be based on Phase II/III data in lupus nephritis and systemic lupus erythematosus, but the safety signal throws a wrench into those carefully laid plans.

As Oppenheimer analysts Kevin DeGeeter and Christopher Holterhoff predict in an October 27 research note, it’s more likely that FDA will ask for full Phase III studies for atacicept, throwing up an unexpected roadblock to approval—and pushing back the timing for a US launch until 2014 at the earliest.

Even if approved, the news has significant commercial implications for ZymoGenetics. An important rationale for atacicept is the expected safety benefit compared to anti-CD20 drugs such as Rituxan. As DeGeeter and Christopher Holterhoff point out, an increased risk for infections may limit the commercial appeal of atacicept in rheumatoid arthritis and multiple sclerosis (both of which are in Phase II studies).

Given the way things are heading these days, it’s a pretty safe bet that FDA won’t look too kindly on a fast track filing for a large molecule with a serious risk of infection. And FDA has all the more reason to be extra cautious, based on a study on biologics safety published in the Journal of the American Medical Association.

The findings aren’t pretty: the probability of a biologic having a safety-related regulatory action is 14% within three years of approval, and 29% within 10 years of approval, Thijs J. Giezen et al. found. Those “safety-related actions” can range from a letter to health care providers about a new safety signal to a black box warning in labeling to a market withdrawal.

When that study is compared to similar studies with small molecules, it’s even more dismal for biologics manufacturers: a study published in JAMA in 2002 found that new chemical entities approved until 1999 had a probability of a black box warning of 10% after 10 years of marketing, compared with the 17% found in the Giezen study.

Whether those kind of studies put pressure on FDA to be more cautious when it comes to large molecule development is anyone’s guess. As we've argued before, FDA's Risk Evaluation & Minimization Strategies should give the agency the confidence to approve products it otherwise might not. But those data certainly don't instill confidence in the regulatory system for biologics.

For individual products like ZymoGenetics’ atacicept, the fall-out is the potential loss of an accelerated BLA filing. But given that many large pharma companies are in the midst of giving themselves an Extreme Biotech Makeover, the JAMA study may give some companies pause. There's no doubt biotech is a risky investment; but Giezen et al. put the safety risk in black and white.

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